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Published on: March 5, 2018
High throughput digital quantification of mRNA abundance in primary human acute myeloid leukemia samples
Jacqueline E Payton1, Nicole R Grieselhuber, Li-Wei Chang
1Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University Medical School, St. Louis, Missouri 63110, USA.
Abstract:
Acute promyelocytic leukemia (APL) is characterized by the t(15;17) chromosomal translocation, which results in fusion of the retinoic acid receptor alpha (RARA) gene to another gene, most commonly promyelocytic leukemia (PML). The resulting fusion protein, PML-RARA, initiates APL, which is a subtype (M3) of acute myeloid leukemia (AML). In this report, we identify a gene expression signature that is specific to M3 samples; it was not found in other AML subtypes and did not simply represent the normal gene expression pattern of primary promyelocytes. To validate this signature for a large number of genes, we tested a recently developed high throughput digital technology (NanoString nCounter). Nearly all of the genes tested demonstrated highly significant concordance with our microarray data (P < 0.05). The validated gene signature reliably identified M3 samples in 2 other AML datasets, and the validated genes were substantially enriched in our mouse model of APL, but not in a cell line that inducibly expressed PML-RARA. These results demonstrate that nCounter is a highly reproducible, customizable system for mRNA quantification using limited amounts of clinical material, which provides a valuable tool for biomarker measurement in low-abundance patient samples.
Insights
Researchers identified a unique gene expression signature for acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia (AML). This discovery, validated using NanoString nCounter technology, aids in APL diagnosis and biomarker measurement.
Area of Science:
- Hematology
- Molecular Biology
- Genomics
Background:
- Acute promyelocytic leukemia (APL) is a subtype (M3) of acute myeloid leukemia (AML).
- APL is defined by the t(15;17) chromosomal translocation, leading to the PML-RARA fusion protein.
- A specific gene expression signature for APL is needed for accurate diagnosis and understanding of the disease.
Purpose of the Study:
- To identify a gene expression signature specific to APL (M3) samples.
- To validate this signature using high-throughput digital technology.
- To assess the utility of the validated signature in clinical settings and research.
Main Methods:
- Identification of a gene expression signature unique to M3 samples, distinct from other AML subtypes and normal promyelocytes.
- Validation of the gene signature using NanoString nCounter high-throughput digital technology.
- Testing the validated signature on independent AML datasets and in a mouse model of APL.
Main Results:
- A highly reproducible gene expression signature specific to APL (M3) was identified.
- NanoString nCounter technology demonstrated high concordance with microarray data (P < 0.05).
- The validated signature accurately identified M3 samples in external datasets and was enriched in a mouse model.
Conclusions:
- The identified gene signature is specific to APL and can reliably distinguish it from other AML subtypes.
- NanoString nCounter is a reproducible and customizable system for mRNA quantification, suitable for limited clinical material.
- This technology offers a valuable tool for biomarker measurement in low-abundance patient samples, aiding APL research and diagnostics.
